An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies

Abstract

Developmental and epileptic encephalopathies (DEEs) are complex conditions characterized primarily by seizures associated with neurodevelopmental and motor deficits. Recent evidence supports sigma-1 receptor modulation in both neuroprotection and antiseizure activity, suggesting that sigma-1 receptors may play a role in the pathogenesis of DEEs, and that targeting this receptor has the potential to positively impact both seizures and non-seizure outcomes in these disorders. Recent studies have demonstrated that the antiseizure medication fenfluramine, a serotonin-releasing drug that also acts as a positive modulator of sigma-1 receptors, reduces seizures and improves everyday executive functions (behavior, emotions, cognition) in patients with Dravet syndrome and Lennox-Gastaut syndrome. Here, we review the evidence for sigma-1 activity in reducing seizure frequency and promoting neuroprotection in the context of DEE pathophysiology and clinical presentation, using fenfluramine as a case example. Challenges and opportunities for future research include developing appropriate models for evaluating sigma-1 receptors in these syndromic epileptic conditions with multisystem involvement and complex clinical presentation.

Keywords: developmental and epileptic encephalopathy; fenfluramine; serotonin receptor; sigma-1 receptor.

Figure 1

Potential mechanism of fenfluramine. Epilepsy is thought to generate an imbalance between inhibitory GABA signaling and excitatory glutamatergic signaling, leading to seizures. In the above figures, the balance between inhibitory and excitatory signaling is indicated by the blue balance beam. (A) Too much glutamate signaling results in seizures (e.g., the right arm of the balance beam moves upward). (B) Balance between inhibition and excitation is restored by the dual activities of fenfluramine: the activity of fenfluramine at 5-HT receptors results in increased GABA signaling, boosting inhibition, while the activity of fenfluramine at the Sigma1R reduces glutamatergic signaling, decreasing excitation. This mechanism is consistent with much, but not all, of the published research and is presented as a working model. 5-HT, serotonin; GABA, gamma aminobutyric acid; Sigma1R, Sigma1 receptor.

Figure 2

Intracellular interactions of Sigma1R chaperone proteins in inactive and active states. In the resting state, Sigma1R associates with the regulatory protein BiP at the ER MAM. During seizures, loss of GABAergic tone results in excessive NMDAR-mediated calcium influx in glutamatergic neurons. The Sigma1R translocates to the plasma membrane or the ER plasmalemmal space, where it interacts with client proteins, including ion channels (e.g., NMDA, sodium, potassium, voltage-regulated chloride), trophic factor receptors, and kinases; interaction with Rac-GTPases promotes dendritic spine formation and affects neuronal redox processes. For comprehensive consideration of intracellular interactions, see Su 2010, Hayashi and Su 2005, Voronin 2020, Rosseaux and Greene 2015, Vavers 2019, and Maurice 2020. BiP, binding immunoglobulin protein; Ca²⁺, calcium; ER, endoplasmic reticulum; GPCR, G-protein−coupled receptor; GTPase, hydrolase enzyme of guanosine triphosphate; IP₃R, inositol triphosphate receptor; MAM, mitochondrial associated membrane; NMDAR, N-methyl-d aspartate.

Figure 3

Activity profile of SOMCL-668 (SOMCL, 10 µM) and fenfluramine (FFA, 25 µM) in 7 dpf zebrafish larvae. (A) Treatment with SOMCL or FFA decreases the locomotor activity of 7 dpf scn1Lab−/− mutants (HO), but not wildtype (WT). Locomotor activity was normalized against VHC-treated scn1Lab−/− mutant larvae and is displayed as percentage ± SD. N = 30 to 60 zebrafish larvae for all experimental conditions. (B) Treatment with SOMCL and FFA reduces the epileptiform brain activity of 7 dpf scn1Lab−/− mutants (HO). The bars represent the numbers of epileptiform events (during 10 min of recording; ± SD) of homozygous scn1Lab−/− mutants (HO) or wildtype scn1Lab+/+ (WT) treated with vehicle (VHC) or SOMCL or FFA, compared to the outcome observed in VHC-treated homozygous scn1a mutants, vehicle control (VHC [HO]). N = 9 to 18 zebrafish larvae for all experimental conditions. Overall, statistical significance is represented by asterisks: ** p < 0.01, and *** p < 0.001 vs. VHC (HO). “No statistical difference” is left blank or is shown by “ns”. Statistical analyses: GraphPad Prism 5 software (GraphPad Software, Inc., San Diego, CA, USA) was used for statistical analyses. (A) Locomotor activity was analyzed by one-way ANOVA and subsequent Dunnett’s multiple comparison tests, as described in Sourbron 2016 and 2017 [23,30]. (B) Electrographic brain activity was analyzed by Mann-Whitney U tests, as was described in Sourbron 2016 and 2017 [23,30].

Figure 4

Biphasic dose response is a characteristic of many Sigma1R ligands. (A) Example dose–response curve showing therapeutic window for a response. (B) Representative examples of Sigma1R agonists and positive modulators following biphasic dose response [22,96,97,98,99].